There have been found various cytokines which are a protein inhibiting manifectation of biofunctions such as immunoresponse, inflammatory reaction and hemopoietic function in biobody, and the structures and activities thereof have gradually been clarified. With such clarification, it has also been made clear that they are effective not only onto the immune system but also onto various biofunctions and have much relevance to generation of biobody, differentiation, homeostasis, and pathological physiology.
Among the cytokines, TNF has been found as an antitumor cytokine and has been expected to be useful as an antitumor agent. However, later on it was found that it is identical with cachectin which is a cachexy-inducing factor. It is reported that TNF has an activity of stimulating production of other cytokines such as IL-1, etc., proliferative activity of fibroblast, endotoxin shock-inducing activity, an activity of promoting the adhesion of leukocytes to endothelium by increasing intercellular adhesion molecules (ICAM-1, ICAM-2) or endothelial leukocyte adhesion molecule-i (ELAM-1), an activity of bone absorption, and an activity of inducing arthritis (e.g. cartilage decomposing activity) cf. Beutler, B., et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989); Akatu, K. & Suda, T., Medical Practice, 8 (9), 1393-1396 (1991)!.
Moreover, it is reported that in bacterial or parasitic infectious diseases, TNF is contained in a higher concentration in blood and cerebrospinal fluid cf. Mituyama, M., IGAKU-NO-AYUMI, 159 (8), 467-470 (1991); and Nakao, M., IGAKU-NO-AYUMI, 159 (8), 471-474 (1991)!. It is also reported that in rheumatoid arthritis, the joint fluid and blood serum have TNF-.alpha. activity cf. Saxne, T., et al., Arthritis Rheum., 31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 (1991); Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990); Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); and Brennan, F. M., et al., Bri. J. Rheum., 31, 293-298 (1992)!.
It is further reported that in patients suffered from a severe respiratory diseases: adult respiratory distress syndrome (ARDS), the phlegm of the patients contain an increased TNF cf. Millar, A. B., et al., Nature, 324, 73 (1986)!, and that TNF participates also in the severity of virus hepatitis cf. Muto, Y. et al., Lancet, ii, 72-74 (1986)!.
It is also reported that the blood concentration of TNF-.alpha. raises in case of myocardial ischemia (e.g. acute myocardial infarction) cf. Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)!, and it is suggested that TNF-.alpha. will participate in such diseases cf. Lefer, A. M., et al, Science, 249, 61-64 (1990)!. It is recently reported that TNF-.alpha. inhibits myocardial contraction cf. Finkel, M. S., et al., Science, 257, 387-389 (1992); and Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)!.
However, there have never been developed a chemo-therapeutic drug which exhibits satisfactory effects on the above-mentioned various diseases such as rheumatoid arthritis, endotoxin shock, or ARDS, and there have merely been used some steroids, antiinflammatory agents, platelet agglutination inhibitors, antibiotics from the nostropic viewpoint. Since it has been suggested the correlation between these diseases and the raising of concentration and activity of TNF-.alpha., it has recently been tried to employ an antibody of TNF-.alpha. in the treatment of these diseases, but it did not give satisfactory result. Thus, it has been desired to find and develop a new type drug for the treatment of these diseases by a new mechanism to inhibit the accelerated production or secretion of TNF-.alpha..
By the way, the carbostyril compounds of the formula I! as shown hereinafter are disclosed in U.S. Pat. No. 5,053,514 as a cardiotonic agent, wherein the processes for the preparation thereof are also disclosed. It is also known that these compounds have myocardial contract increasing activity (i.e. positive inotropic activity), coronary blood flow increasing activity, hypotensive activity, an activity of inhibiting blood vessel contract induced by norepinephrine, and antiinflammatory activity (cf. the above U.S. Patent as well as U.S. Pat. Nos. 5,266,577 and 5,385,914), and are useful as a thrombosis treating agent, phosphodiesterase inhibitor, cerebral circulatory improving agent (cf. U.S. Pat. No. 5,401,754), as an antiarrhythmic agent (cf. WO 94/06427), and as an anti-histaminic agent (cf. Japanese Patent First Publication (Kokai) No. 56-8319). It is also reported that a compound inclusive in the carbostyril compounds of the formula I!: i.e. 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril has hemodynamic effects in patients with advanced heart failure (cf. Journal of Cardiac Failure, Vol. 1 No. 1 pp. 57-62, Oct. 1994). However, these literatures do not teach or even suggest that the carbostyril compounds have the activities of inhibiting production or secretion of TNF-.alpha..